In 2010 there were an estimated 8.8 million incident cases of tuberculosis (TB) globally, with 2.3 million of these reported in Africa, 1.1 million deats among HIV-negative cases of TB and an additional 0.35 million deaths among people who were HIV-positive. The complex relationship between TB pathogen, host, and drug exposure in the pathogenesis of TB is poorly understood. The treatment regimen that is currently recommended by WHO for new cases of drug-susceptible TB is highly efficacious, with cure rates of around 90% in HIV-negative patients. However, even if all new TB cases were treated and patients were adherent to the treatment, there would still be 10% of patients (i.e. 880,000 patients worldwide, 230,000 patients in Africa) who fail to respond to treatment. Even if adherent to treatment, a proportion of patients, with rifampicin sensitive TB, are slow to respond to medication or are non-responders. The problem is even more complex and serious in HIV infected patients where the efficacy of the current treatments appears to be lower. Still other patients can be treated successfully, but will experience toxicity and thus treatment interruptions. While several potential determinants of the variable response to drug treatment are recognized (e.g. sex, age, ethnicity), much of the variability in response to anti-tuberculosis drugs remains unexplained. In recent years there has been a rapid development in the understanding of the genetics underlying inter- individual differences in drug metabolism and treatment efficacy. The field of pharmacogenetics encompasses the study of the heterogeneity in genes related to drug transporters, drug metabolizing enzymes and drug targets, in the context of efficacy of treatment and adverse drug reactions. Few studies have been conducted to explore this field for TB disease. Through this study we aim to explore and determine host genetic factors contributing to pharmacokinetic (i.e. drug concentration) and dynamic (i.e. treatment outcome) variability in TB patients. The """"""""RAFAgene"""""""" study is a 4 year project which will be nested within two multi-country randomized phase III tuberculosis treatment trials, the OFLOTUB and RAFA trials (reg numbers NCT00216385 and PACTR 201105000291300) conducted in Sub-Saharan Africa. Patients enrolled in the pharmacokinetic studies within these 2 trials will be sampled for genetic analysis (genome-wide and targeted SNPs screening with in vitro confirmation of the biological plausibility of the association between pharmacokinetic and genetic characteristics). The proposed project is led by Dr. Dissou Affolabi at the National Hospital for TB and Pulmonary (NHTPD) with partners from the National TB program in Senegal, the University Ignace Deen in Guinea, the University of Cape Town (SA), the Medical Research Council in Durban (South Africa), the University of Liverpool UK and the London School of Hygiene and Tropical Medicine UK.
While efficient, the current standard tuberculosis treatments fail in approximately 10% of patients, corresponding to almost 1 million individuals per year worldwide, despite good treatment adherence. Several potential determinants of the variable responses to some drug treatment are recognized, however, much of the variability to anti-tuberculosis drugs remains unexplained and could be partly due to host genetic variability.
We aim with the proposed study to explore the role of host genetics and aim to build on the few pharmacogenetics studies which have been conducted in the context of tuberculosis treatment so far.
|McIlleron, Helen; Abdel-Rahman, Susan; Dave, Joel Alex et al. (2015) Special populations and pharmacogenetic issues in tuberculosis drug development and clinical research. J Infect Dis 211 Suppl 3:S115-25|